Brain tumors are the second leading cause of cancer-related deaths in children and fourth in middle-aged man. Malignant gliomas remain uniformly fatal underscoring the urgent need for new, more effective treatments. More effective therapies coupled with improved imaging information would provide important opportunities to improve care and individualize treatments. Results from pre-clinical studies funded by the Phase I award using a direct injection of BCNU dissolved in ethanol (DTI-015) have revealed significant therapeutic efficacy compared to systemic delivery of BCNU. Moreover, recent results obtained from two clinical Phase I/II trials by Direct Therapeutics, Inc. have generated a great deal of excitement for the use of DTI-015 for the treatment of malignant brain tumors. A significant limitation of the DTI-015 formulation is that The toxicity of the absolute ethanol limits the scope of its applicability to solid, small (3-4 cm) well Circumscribed tumors in humans. In an effort to treat larger as well as disseminated, infiltrating malignant gliomas, we propose to investigate the use of alternate drug delivery vehicles, which are proposed to have reduced toxicity and the potential to deliver BCNU over a larger tissue volume. In this Phase II proposal, we will use a rodent glioma model to optimize the BCNU formulation to achieve maximal delivery and therapeutic efficacy. Phase I award results demonstrated a tumoral transient vascular collapse after administration of DTI-015 that may play a significant role in the efficacy of the agent due to the retention of BCNU within the tumor tissue. The ability of alternate vehicles to induce this vascular collapse without toxicity resulting in an improvement in therapeutic efficacy will be investigated. The proposed studies will be facilitated through the use of noninvasive serial magnetic resonance imaging to evaluate the dynamic distribution of the solvent vehicle as well as the therapeutic effectiveness by diffusion weighted MRI. The use of MRI will prove beneficial for subsequent translation of an optimized formulation into clinical trials. Although the present study is focused on the treatment of brain tumors, the successful local treatment of this disease would motivate future clinical trials to other tumor sites including breast, prostate and pancreas.